The ACC's leading rusher, Montel Harris, rushed for 144 yards on 36 carries and the Tigers suffered through a series of self-inflicted miscues to help lift the Eagles to the upset win, 16-10.
Freshman quarterback Chase Rettig also threw a 36-yard touchdown pass to Harris and Nate Freese made a pair of field goals to pace Boston College (3-5, 1-4 ACC).
The only touchdown of the game for the Tigers came on Rashard Hall's 52-yard interception return for a touchdown on Rettig's first pass of the day.
Clemson appeared to be in control early before a roughing the passer penalty on third-and-26 and a fumbled kick return by Jamie Harper changed the complexion of the game.
Trailing 10-3, the Eagles quickly capitalized.
Freese kicked a 36-yard field goal as the drive stalled, cutting it to 10-6 before Steele Divitto recovered a fumble on the ensuing kickoff.
The ball bounced several times on the ground before reaching the 20 yard line before Harper tried to scoop it up, but he never could fully gain control- leading to the fumble recovery for the Eagles.
The very next play, Rettig hit Harris, who was wide open, for the go-ahead score.
"The turnover on special teams and then they hit the wheel route for a touchdown that obviously was a critical, critical play," head coach Dabo Swinney said afterwards.
Freese would add another 36-yard field goal as time expired in the first half to give B.C. a 16-10 lead.
After giving up nearly 200 yards of total offense in the first half, the Clemson defense tightened things up in the second, but the offense never quite got going.
The only touchdown of the game for the Tigers came on Rashard Hall's 52-yard interception return for a touchdown. (Roy Philpott)
Still, after a scoreless third quarter, the Tigers had multiple opportunities in the fourth.
With Clemson facing a third-and-16 at the Boston College 19 early in the final period, Kyle Parker unexplainably threw a pass across his body to the middle of the field where it was intercepted by B.C. cornerback Donnie Fletcher.
"if I could take it back I would," Parker said of the play. "Looking at it from my perspective, we were going into the wind and was quite a long kick. I wanted to give our guys at least a chance to make it and it didn't happen. That was the thought process.
"We were going into the wind and I wanted to give our guys a chance to make a play instead of throwing it away and settling. I wanted to give them the opportunity."
The Tigers moved into BC territory again later on, but Dwayne Allen was tackled a yard short of the first down on fourth-and-7.
B.C. linebacker Luke Kuechley then hammered home the nail in the coffin by intercepting Parker one last time with 1:42 left.
"The offense could absolutely not do anything today. We couldn't capitalize. When we had opportunities we couldn't score in the red zone and we had been a pretty good red zone team. But when you are 0-for-3 down there you aren't going to win," Swinney said.
Clemson kicker Chandler Catanzaro was also off after making an early field goal - missing from 41 and 36 yards.
Swinney said afterwards back up Richard Jackson would have kicked the next field goal, had Clemson had the opportunity.
Andre Ellington, the ACC's third leading rusher coming into Saturday, ran for just 42 yards on 14 attempts while Kyle Parker was 21 for 39 for 176 with the two interceptions.
Offensive coordinator Billy Napier shouldered the bulk of the blame for the lack of production afterwards.
"Ultimately, those were obviously bad decisions," he said of Parker's two fourth-quarter interceptions. "I've got to coach him better because when he does things like that, it's a reflection on me that we aren't getting it done. I've got to coach him to manage the game better. Those were costly mistakes for sure."
Indeed they were.
Now sitting at 4-4 overall and 2-3 in league play, the Tigers have been virtually eliminated from returning to the ACC Championship game.
"It hurts," offensive lineman Landon Walker said. "We knew this was going to be a tough game against these guys coming in because it always is. But we expected to win. Now we've got to regroup, go back and figure out what went wrong and get ready for next week."
Clemson returns to action next week against N.C. State at Memorial Stadium.